Recent discoveries have shed new light onto immunoglobulin M (IgM), an ancient antibody class preserved throughout evolution in all vertebrates. First, IgM - long thought to be a perfect pentamer - ...was shown to be asymmetric, resembling a quasi-hexamer missing one monomer and containing a gap. Second, this gap allows IgM to serve as carrier of a specific host protein, apoptosis inhibitor of macrophages (AIM), which is released to promote removal of dead-cell debris, cancer cells, or pathogens. Third, recombinant IgM delivered mucosally by passive immunization gave proof-of-concept that this antibody class can prevent mucosal simian-human immunodeficiency virus transmission in non-human primates. Finally, IgM's role in adaptive immunity goes beyond being only a first defender to respond to pathogen invasion, as long-lived IgM plasma cells have been observed predominantly residing in the spleen. In fact, IgM produced by such cells contained somatic hypermutations and was linked to protection against lethal influenza virus challenge in murine models. Importantly, such long-lived IgM plasma cells had been induced by immunization 1 year before challenge. Together, new data on IgM function raise the possibility that vaccine strategies aimed at preventing virus acquisition could include this ancient weapon.
Autosomal dominant gain of function mutations in the gene encoding PI3K p110δ were recently associated with a novel combined immune deficiency characterized by recurrent sinopulmonary infections, CD4 ...lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. A subset of affected patients also had elevated serum IgM. Here we describe three patients in two families who were diagnosed with HIGM at a young age and were recently found to carry heterozygous mutations in
PIK3CD
. These patients had an abnormal circulating B cell distribution featuring a preponderance of early transitional (T1) B cells and plasmablasts. When stimulated in vitro,
PIK3CD
mutated B cells were able to secrete class-switched immunoglobulins. This finding implies that the patients’ elevated serum IgM levels were unlikely a product of an intrinsic B cell functional inability to class switch. All three patients developed malignant lymphoproliferative syndromes that were not associated with EBV. Thus, we identified a novel subset of patients with
PIK3CD
mutations associated with HIGM, despite indications of preserved in vitro B cell class switch recombination, as well as susceptibility to non-EBV-associated malignancies.
Hepatitis E virus (HEV) is the leading cause of acute hepatitis worldwide. The minimum criterion for diagnosis of acute infection is detection of anti‐HEV antibodies, although there are scant data on ...IgM duration. Our aim was to assess the persistence of HEV markers after acute self‐limited hepatitis E. HEV serological tests (IgM by Mikrogen and Wantai and HEV‐Ag) and HEV RNA were carried out in two cohorts: (a) patients with prior acute hepatitis E (ALT >10 x ULN plus positive IgM ± HEV RNA) currently self‐limited and (b) 50 blood donors with positive HEV RNA. Among 25 cases of prior acute hepatitis E, after a median follow‐up of 34 months, all presented undetectable HEV RNA. However, anti‐HEV IgM remained detectable in 14 (56%) by Mikrogen, 6 (24%) by Wantai and none for HEV‐Ag. Anti‐HEV IgM tested positive in 80%‐100% within the second year and 17%‐42% over 3 years later, by Wantai and Mikrogen, respectively. Among HEV RNA‐positive donors, 12 (25%) tested positive for either IgM by Mikrogen or Wantai, 9 (18%) for both and 18 (36%) for HEV‐Ag. HEV‐Ag positivity was more likely as HEV RNA was higher (14% if <2.2 log IU/mL; 64% if RNA ≥ 3.7). Overall, HEV‐Ag performed best, with a positive predictive value of 100% and diagnostic accuracy of 57%. Anti‐HEV IgM exhibited unexpectedly long persistence after a self‐limited acute hepatitis E. HEV‐Ag had the best performance and could be especially useful in settings where HEV RNA is not available.
Human marginal zone B cells Weill, Jean-Claude; Weller, Sandra; Reynaud, Claude-Agnès
Annual review of immunology,
01/2009, Letnik:
27
Journal Article
Recenzirano
Human marginal zone (MZ) B cells are, in a sense, a new entity. Although they share many properties with their mouse counterpart, they also display striking differences, such as the capacity to ...recirculate and the presence of somatic mutations in their B cell receptor. These differences are the reason they are often not considered a separate, rodent-like B cell lineage, but rather are considered IgM memory B cells. We review here our present knowledge concerning this subset and the arguments in favor of the proposition that humans have evolved for their MZ B cell compartment a separate B cell population that develops and diversifies its Ig receptor during ontogeny outside T-dependent or T-independent immune responses.
D40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis has rarely been reported, and its genotype-phenotypic correlation remains elusive.
We describe a five-month-old boy ...with CD40LG mutation (c.516T > A, p.Tyr172Ter) X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis as the first manifestation. The patient completely recovered after immunotherapy and allogeneic hematopoietic stem cell transplantation. In addition, four previously reported patients with CD40LG mutation with pulmonary alveolar proteinosis were also analyzed. All of these patients presented with early onset of pulmonary infections and a good response to immunotherapy. The structural model of CD40LG indicated that all mutations caused the X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis to be located within the tumor necrosis factor homology domain.
A case was presented, and the characteristics of four cases of CD40LG-associated X-linked hyper-IgM syndrome with pulmonary alveolar proteinosis were summarized. The variant locations may explain the phenotypic heterogeneity of patients with the CD40LG mutation.
The outbreak of the novel coronavirus disease (COVID‐19) quickly spread all over China and to more than 20 other countries. Although the virus (severe acute respiratory syndrome ...coronavirus SARS‐Cov‐2) nucleic acid real‐time polymerase chain reaction (PCR) test has become the standard method for diagnosis of SARS‐CoV‐2 infection, these real‐time PCR test kits have many limitations. In addition, high false‐negative rates were reported. There is an urgent need for an accurate and rapid test method to quickly identify a large number of infected patients and asymptomatic carriers to prevent virus transmission and assure timely treatment of patients. We have developed a rapid and simple point‐of‐care lateral flow immunoassay that can detect immunoglobulin M (IgM) and IgG antibodies simultaneously against SARS‐CoV‐2 virus in human blood within 15 minutes which can detect patients at different infection stages. With this test kit, we carried out clinical studies to validate its clinical efficacy uses. The clinical detection sensitivity and specificity of this test were measured using blood samples collected from 397 PCR confirmed COVID‐19 patients and 128 negative patients at eight different clinical sites. The overall testing sensitivity was 88.66% and specificity was 90.63%. In addition, we evaluated clinical diagnosis results obtained from different types of venous and fingerstick blood samples. The results indicated great detection consistency among samples from fingerstick blood, serum and plasma of venous blood. The IgM‐IgG combined assay has better utility and sensitivity compared with a single IgM or IgG test. It can be used for the rapid screening of SARS‐CoV‐2 carriers, symptomatic or asymptomatic, in hospitals, clinics, and test laboratories.
Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from ...the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the
CD40L
gene (
CD40LG
). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by
Mycoplasma pneumoniae
,
Serratia marcescens
or
Aspergillus sp.
and diarrhea caused by
Microsporidium sp.
or
Isospora belli.
Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
Chemokine C-X-C motif ligand 13 (CXCL13), originally identified as a B-lymphocyte chemokine, exerts a crucial role in the chemotaxis of B cells through its receptor CXCR5. Although the presence of ...CXCL13/CXCR5 had been reported in various teleost fish species, its impact on IgM+ B cell still remains unknown. In this study, we investigated the role of chemokine CXCL13 and its receptor CXCR5 in the chemotaxis of IgM+ B cells in Nile tilapia (Oreochromis niloticus). We identified and characterized two isotypes of OnCXCL13 (OnCXCL13a and OnCXCL13b) and CXCR5 (OnCXCR5) in Nile tilapia. The OnCXCL13 is characterized with a typical small cytokine CXC domain and four cysteine, in which the first two cysteines separated by a random amino acid residue, and OnCXCR5 is characterized by seven α-helical transmembrane domains. Both OnCXCL13 and OnCXCR5 were found to be expressed in various tissues and lymphocytes, with the highest expression in the spleen (SPL). Their expression in IgM+ B cells was significantly higher than that in IgM− lymphocytes. Following Streptococcus agalactiae infection, the expressions of OnCXCL13a and OnCXCL13b were up-regulated in peripheral blood (PBL), SPL and head kidney (HK), while OnCXCR5 was significantly up-regulated in SPL and HK. We also found that the recombinant OnCXCL13 proteins had strong chemotactic activity on IgM+ B cells, which could be inhibited by blocking OnCXCR5 with anti-OnCXCR5 antibody. Mechanistically, incubation with OnCXCL13 resulted in the up-regulation of AKT and STAT3 phosphorylation in IgM+ B cells, which could be attenuated by specific inhibitors of AKT and STAT3. Inhibition of AKT and STAT3 also weakened the chemotaxis of OnCXCL13 on IgM+ B cells. Our results suggest that the CXCL13/CXCR5 axis participates in the immune response of tilapia and mediates the chemotaxis of IgM+ B cells, providing insights into the potential role of this axis in bacterial infection and teleost B cell migration.
•The CXCL13 (OnCXCL13a and OnCXCL13b) and CXCR5 (OnCXCR5) genes are identified in Nile tilapia (Oreochromis niloticus).•OnCXCL13 and OnCXCR5 are highly expressed in the spleen and lymphocytes, particularly in IgM+ B cells.•Expression of OnCXCL13 and OnCXCR5 is significantly up-regulated upon Streptococcus agalactiae challenge.•OnCXCL13 interacts with OnCXCR5 to mediate IgM+ B cell migration by activating the AKT and STAT3 signaling pathways.
Loss of CD40 ligand (CD40L) expression or function results in X-linked hyper-immunoglobulin (Ig)M syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin ...class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter–dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder. Here, we report efficient, on-target, homology-directed repair (HDR) editing of the CD40LG locus in primary human T cells using a combination of a transcription activator-like effector nuclease–induced double-strand break and a donor template delivered by recombinant adeno-associated virus. HDR-mediated insertion of a coding sequence (green fluorescent protein or CD40L) upstream of the translation start site within exon 1 allowed transgene expression to be regulated by endogenous CD40LG promoter/enhancer elements. Additionally, inclusion of the CD40LG 3′-untranslated region in the transgene preserved posttranscriptional regulation. Expression kinetics of the transgene paralleled that of endogenous CD40L in unedited T cells, both at rest and in response to T-cell stimulation. The use of this method to edit X-HIGM patient T cells restored normal expression of CD40L and CD40–murine IgG Fc fusion protein (CD40-muIg) binding, and rescued IgG class switching of naive B cells in vitro. These results demonstrate the feasibility of engineered nuclease-directed gene repair to restore endogenously regulated CD40L, and the potential for its use in T-cell therapy for X-HIGM syndrome.
•The CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA.•Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching.
Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting ...of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.
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•AIDG133V mice lack CSR and SHM and model the pathology of hyper-IgM syndrome•AIDG133V does not bind G4 nucleic acids but is catalytically active•AIDG133V has impaired chromatin localization, but enforced DNA targeting rescues CSR•AID localizes to MHCII genes, and its activity may regulate MHCII gene expression
Yewdell et al. examine the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo using mice bearing a mutation in Aicda found in hyper-IgM syndrome patients. Their findings reveal a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to B cell function.
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